This project has already defined a new syndrome characterized by chronic lymphadenopathy, splenomegaly and autoimmune phenomena. The first affected patient had a gain-of-function mutation on the gene NRAS. This resulted in the hyperactivation of the RAS-RAF-ERK pathway and suppression of the pro-apoptotic protein named BIM. This in turn resulted in defective T cell apoptosis after IL-2 withdrawal, but normal T cell and B cell apoptosis in response to staurosporine, etoposide, cisplatin and radiation as well as a normal Fas pathway induction of apoptosis. The low levels of BIM also affected the apoptosis induced by T-cell reactivation. Since the initial description we have now studied a total of three patients with somatic NRAS mutations all of whom have defects in T cell apoptotic death associated with cytokine withdrawal. The important clincial observation is that all three patients presented early in childhood with a disorder that has many features of acute myelomonocytic leukemia (AMML) but it is not an aggressive or malignant disorder unlike AMML. In fact the marked monocytosis and bone marrow changes improve without therapy while AMML requires bone marrow transplantation. This distinction is obviously of great clinical importance and we are now fielding additional patient samples in order to better define this somatic NRAS mutation disorder that overlaps with ALPS. The results of these expanded studies will be reported upon completion of the intial studies. More recently, we have identified two other patients with clinical manifestations of ALPS and defective cytokine-withdrawal induced apoptosis which harbored activating mutations in the KRAS gene. As a group, patients with KRAS and NRAS mutations are distinct from the typical ALPS patients, and we suggested the name RAS-Associated Autoimmune Leukoproliferative Disorder (RALD) for the disease. We have evaluated an additional four patients with NRAS or KRAS heterozygoous defects and are now in the process of providing a more definitive clinical phenotype of RALD. We have also sequenced whole exomes of a group of ALPS-like patients and have not identified any additional genetic defects linked to this group of patients.